JPS5838210A - Preparation for rectal administration - Google Patents

Abstract

PURPOSE:A preparation for rectal administration that is made by adding at least one selected from 1-5C carboxylic acids, inorganic acids, their alkali metal salts and alkaline earth metal salts to increase the absorbability of hard absorbable medicines, thus being especially useful for patients with esophagus cancer. CONSTITUTION:The objective preparation is made by adding at least one selected from 1-5C carboxylic acids such as acetic or propioninc acid, inorganic acids, their alkalie metal or alkaline earth metal salts to a medicine hard absorbable from rectum such as a combination of uracil and tegafur or suxibuzone. Further, at least one of aliphatic alcohols such as tris(hydroxymethyl)aminomethane, at least one of surface active agents, starch, cellulose or their derivative are added to permit the reduction in the amount of the acid or its salt to be added or increase in the absorption of the active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a preparation for rectal administration, which is characterized by incorporating a specific compound into a drug that can be absorbed into the rectum.

Many of the known drugs are difficult to absorb from the rectum, making it difficult to administer them rectally, and their clinical administration route is limited to the oral route. In addition, there is a desire to develop a formulation that can be administered to patients who are unable to take oral intake due to esophageal passage obstruction, etc.
It's ro. For example, suxibucin is a non-steroidal anti-inflammatory drug derived from phenylbutacin, and is an excellent drug that reduces the gastrointestinal side effects seen with phenylbutacin, but a rectally administered formulation is still under development due to poor absorption. Although the combination drug of uracil and tegafur is an excellent antitumor agent with synergistic antitumor effects, it may be difficult to swallow or pass during oral administration, especially in patients with cancer such as esophageal cancer. The development of a preparation for rectal administration is awaited, but it has the disadvantage that sufficient absorption cannot be obtained when administered rectally.

Therefore, the present inventors conducted a study on compositions for rectal administration in order to improve the absorbability from the rectum. Conventionally, in order to improve absorption from the rectum, methods such as use of water-based surfactants, making oily bases hydrophilic, and use of hydrophilic bases have been reported (J, Phmrm.

Sc 1.66 (7), 9515 (1977), Yakuchu 88 (ri 67 (1978)).

Cl1n, Res, 25(3) 886A (19
77), J. Pharm, Dyn.

8, 24 (1980), Japanese Patent Publication 1982-1
188. Japanese Patent Publication No. 515-8456. Japanese Patent Publication wB52-442221). However, the conventional technology has not been able to achieve the expected sufficient absorption promoting effect and has not been put into practical use. Therefore, the present inventors have completed the present invention as a result of intensive research in order to solve this drawback. reached.

That is, the present invention is a drug absorption method characterized by adding at least one carboxylic acid or inorganic acid having 1 to 5 carbon atoms, or an alkali metal salt or alkaline earth metal salt thereof to a drug that is difficult to absorb from the rectum. The present invention relates to preparations for rectal administration that have the remarkable effect of increasing absorption rate and rapid absorption rate, and by further adding fatty alcohol amines, hydrophilic surfactants, starch, cellulose or derivatives thereof to these preparations, The present invention relates to a preparation for rectal administration in which the amount of the above-mentioned acids or their salts added is significantly reduced and the amount of drug absorbed is increased.

In the present invention, various drugs that can be absorbed into the rectum can be used, and specific examples include a combination of uracil and tegafur, and suxibucin.

Examples of carboxylic acids having 1 to 6 carbon atoms used in the present invention include acetic acid, propionic acid, butyric acid, valeric acid, acrylic acid, methacrylic acid, oxalic acid, malonic acid, succinic acid, tartaric acid, glutaric acid, maleic acid, and fumaric acid. acids such as glycolic acid, lactic acid, glyceric acid, and pyruvic acid; inorganic acids such as carbonic acid and phosphoric acid; and alkali metal salts or alkaline earth metal salts thereof such as sodium salts, potassium salts, magnesium salts, Examples include calcium salts. These can be used alone or in combination, and the amount used is from less than the equivalent mole to the active ingredient of the drug, preferably 411/1 to 1/4% pw, [1/4% pw, [1/4% pw, /g o o -1/s, especially /so~
/10 (weight) is desirable.

Examples of the aliphatic alcohol amines used in the present invention include tris(hydroxymethyl)amitsumethane, monoethanolamine, triethanolamine, etc., and the amount used is determined based on the above-mentioned amount or their salts as the active ingredient of the drug. On the other hand, from less than equimolar to 1. '164
L < it ”/j −1/44l, for the entire drug, ”/! 00-”15. Especially l/6o~1/1
0 (weight) is desirable.

The surfactant used in the present invention may be any of ionic surfactants, nonionic surfactants, and other natural surfactants. Examples of ionic surfactants include nonionic surfactants such as sodium lauryl sulfate. As a surfactant, for example, Tween 80 (manufactured by Polio Hiriko Atlas Co., Ltd.) is used.
Trademark (hereinafter the same), Emazol 1180. emazol 8
180゜Nilacol 10 (manufactured by Nikko Chemicals Co., Ltd.), poly-9 ethylene glycol fatty acid esters (e.g., Nikko Chemicals Co., Ltd., Niracol MY, S-40 (cetomacrocol), etc.), polyoxyethylene alkyl ethers [e.g. , made by Hitoko Atlas Co., Ltd., Emulken 120. Emulgen 22o1 Emulgen 109P, etc.), polyoxyethylene acyl esters (e.g., manufactured by Hitoko Atlas Co., Ltd., Emanon 1112, Emanon 8116, Emanon 4116)
etc.], and those with an HLB of 10 to 2 degrees are preferable, and those with an HLB of about 12 to 16 degrees are particularly preferable. Other natural surfactants include phospholipids such as lecithin, cholesterol, saponins, cholic acids and their salts. The amount of these surfactants used is approximately 0.05 of the base material.
~! 0% (by weight) is preferred, especially about 1-6% (by weight)
is preferred, and one or more of these surfactants can be used in combination.

Examples of starch, cellulose, or derivatives thereof used in the present invention include corn starch, potato starch, crystalline cellulose, methylcellulose, and carboxymethylcellulose. The amount used is preferably about 10-50% (by weight) of the base, particularly about 20-50% (by weight) of the base.
8o (weight) is preferred.

The dosage form for rectal administration may be solid at room temperature or an anal half-split type that melts at body temperature, or an ointment-like or liquid form dispersed in a liquid base using a soft capsule or a syringe for rectal administration. It may also be in the form of a dosage form for administration.

As the base for the drug used in the present invention, conventionally known bases can be used, for example, either hydrophilic or lipophilic bases may be used. As the hydrophilic base, macrogols of various molecular weights can be used. , preferably a molecular weight of about 300 to 200
01j) Macrogol, polyacrylic acid gel, etc., and lipophilic bases such as arachis oil, coconut oil, soybean oil, olive oil, cacao butter, etc., or these modified by hydrogenation, acetylation, fractional extraction, etc. or esters of fatty acids and glycerin having 6 to 80 carbon atoms, such as Dynamite Nobel, Witepsol, Miglyol (all trademarks), etc. Zero or more bases may be used alone or two or more types. May be used in combination with
The amount of base to be used is approximately 1 to 20 fi for the drug used! r
, especially about 2 to 10 times (by weight).

In carrying out the present invention, in the case of a solid base, it is dissolved or melted, and in the case of a liquid base, it is used.

It is possible to add crystals or crushed main medicinal powder and additives to the TT product, disperse it evenly, and mold it according to a known manufacturing method such as halving.

The dosage of the drug of the present invention varies depending on the patient's symptoms, weight, age, etc. - Although it cannot be generally limited, the dosage of the active ingredient of the drug is usually about 10 to 100 g per day for adults.
It is preferable to set the amount within the range of F.

Next, examples and experimental examples of the present invention will be shown.

Example 1 Witepsol W-85 (manufactured by Dynamite Nobel, high-grade salty acid glyceride) 10F was melted at about 40°, and then Sukibucin 2.5v% sodium dihydrogen phosphate o, tp, phosphoric acid 1 water 112 Sodium 0.2F
After stirring well and homogeneously dispersing, dispense into one total dosage form with an internal volume of 1.6F.

Example 2 Witepsol W-85,10F was melted at about 40', then Suxibucin 25f, sodium dihydrogen phosphate o
, ty, add 0.15F of disodium monohydrogen phosphate and 0.1v of cholesterol, stir well to disperse it evenly, and then stir it to reduce the content of 16 to 1.62.
Dispense into all dosage forms.

Example 8? Melt D Gol 184G and top at about 66℃, then add Sukibucin 16F and Sodium dihydrogen phosphate 01p.
, disodium hydrogen phosphate o, 1f, Tween 800
．． Add 2F and stir well to evenly disperse, then add 1
Dispense into 1.6F total dosage form.

Example 4 Witepsol W-86.8f was melted at about 40°C, followed by 4.1 g of uracil and 1.8 F of tegafur.

Sodium hydrogen oxide 2-89. Sodium carbonate 1.22
After adding and stirring well to uniformly disperse, dispense into one total dosage form with an internal volume of 2.62.

Example 6 Witepsol W-85,10y was melted to about 40"0"t", then Uracil 4.1f, Tegafur t, sp.

Sodium hydrocarbon 2.55', sodium electorate 1.0
1. Add 0.2g of setomarogol and stir well to disperse it evenly. ．． Dispense into 89 total dosage forms.

Example 6 Witepsol W-86, 10F was melted at about 40°C,
Next, Sukibucin 165', ) Lis(hydroxymethyl)aminomethane 1.88F, Tartaric acid 0.86, Avicel 101 (manufactured by Asahi Kasei Corporation, crystalline cellulose>o,
Add 5y and stir well to evenly distribute. While stirring, dispense the mixture into one 1.6y total dosage form.

Experimental Example 1 The formulation for rectal administration of the present invention obtained in Example 1.2.8 and a dispersion molded version of squibucin in Witepsol W-85 (control) were administered rectally to Peagle dogs (6 dogs per group), Blood concentrations over time were compared. Administration method is 1
After thoroughly removing the feces remaining in the am and excess water, the molded halves were administered to Peagle-sized animals that had been fasted for 6 hours. The dose was 20 m to body weight as suxibucin. To measure the blood concentration, blood was collected from the forelimb vein over time, and phenylbutacin, the active ingredient of squibucin, was quantified by gas chromatography on the plasma obtained by a conventional method.

The results are shown in Table 1.

Experimental Example 2 The preparation for rectal administration of the present invention obtained in Example 4.5 and the mixture of uracil and tegafur were combined with Uitepsol! -115
A dispersion molded product (control) was administered rectally to rats (6 animals per group), and the blood concentration over time was compared. The administration method was to administer molded halves to rats that had been fasted for 16 hours. The dose was 60 mυ to body weight as tegafur.

In addition, the blood concentration is measured by collecting blood from the stratified vena cava of rats over time and using the standard method! Tegafur and uracil were determined by high performance liquid chromatography and mass gas chromatography, respectively. result 1
12.

In Table 1, AUG means area under plasma concentration.

Procedural amendment (0 phantom Showa 1986, month, day 698 Commissioner of the Patent Office Shima 8 Haruki Tono 1, Indication of the case Order of patents filed on August 31, 1988 "" Name of iq Preparation for rectal administration 3, Person making the amendment Relationship to the incident Address: 9, 2, Kanda Tsukasa-cho, Chiyoda-ku, Tokyo Name: Ohshi Pharmaceutical Co., Ltd., 10: Agent: 2-8 Maru Building, Sone@I, Kita-ku, Osaka, 530 Telephone: 06 (365) 0170 6. The number of inventions increased by the amendment 7. Contents of the amendment to be amended 1. The statement "Dispense" in line 8 at the bottom of page 14 of the specification is corrected as follows. .

“Dispense.

Example 7 Quitepsol W-85,8,96f was melted at about 40 DC, and then 2.68 t of monosodium salt of Crasil was prepared.
, Tegafu I 1t, Sodium dihydrogen phosphate 2.4
f, plus Tween 80.0.1 f.

After stirring well and dispersing it evenly, the contents of 1 piece are about 2 servings.
．． Dispense into 52 halved molds. "(that's all)

Claims (1)

[Claims] (1) A drug that is difficult to absorb from the rectum contains one or more carboxylic acids having 1 to 5 carbon atoms, inorganic acids, or alkali metal salts or alkaline earth metal salts thereof. Characteristic rectally administered MIkl agent. (It is recommended that drugs that are difficult to absorb from the rectum contain one or more carboxylic acids, inorganic acids, or alkali metal salts or alkaline earth metal salts thereof having 1 to ls carbon atoms, and one or more aliphatic alcohol amines). Characteristic preparations for rectal administration. (3) From IEI), a poorly absorbed drug is combined with one or more carboxylic acids having 1 to 6 carbon atoms, inorganic acids, or alkali metal salts or alkaline earth metal salts thereof and surface active agents. 1. A preparation for rectal administration, characterized in that it contains one or more types of agents. (4) Treated in an absorbable drug from the rectum with one or more carboxylic acids having 1 to 6 teeth, inorganic acids, or their alkali metal salts or alkaline earth metal salts, and one or more starch, cellulose, or their derivatives. A preparation for rectal administration, characterized in that: (5) The preparation for rectal administration according to any one of claims 1 to 4, wherein the drug that can be absorbed from the rectum is a combination of uracil and tegafur. (6) The preparation for rectal administration according to any one of claims 1 to 4, wherein the drug that is poorly absorbed from the rectum is suxibucin.